1. Antiphospholipid Antibody
Syndrome
Dr.W A P S R Weerarathna
Registrar in Medicine
WD 10/02

2. Objectives…
• APLS overview
• Revised classification criteria for APLS
• Presentation/clinical manifestations of APLS
• Other specific subtypes of APLS-CAPS/SNAP
• Management guidelines for APLS
• Summary
• References

3. APS is more common in women (5:1 ).
Females -more frequently -arthritis, livedo reticularis, and
migraine
Males -myocardial infarction, epilepsy and lower extremity
arterial thrombosis .
Mean age of onset -31 years
AcA-associated thrombosis- more common than LA-
associated thrombosis, with a ratio of 5:1

4. Primary APLS -aPL in patients with idiopathic
thrombosis.
Secondary APS -autoimmune disorders (SLE
and RA) and thrombosis is found to have aPL.

5. Common autoimmune rheumatic diseases with
aPL antibodies:
• SLE - 25-50%
• Sjogren’s syndrome – 42%
• Rheumatoid arthritis – 33%
• Autoimmune thrombocytopenic purpura - 30%
• Autoimmune hemolytic anemia - Unknown
• Psoriatic arthritis – 28%
• Systemic sclerosis – 25%
• Mixed connective-tissue disease - 22%
• Polymyalgia rheumatica or Giant cell arteritis - 20%
• Behcet syndrome - 20%

6. Revised classification criteria for APLS
one clinical criteria and one laboratory test=
clinical criteria:
1. Vascular thrombosis
One or more clinical episode of arterial, venous or
small-vessel thrombosis.

7. 2. Pregnancy morbidity=
(a) One or more unexplained deaths of morphologically normal
fetuses >/= 10th week, or
(b) One or more premature births of morphologically normal
neonates <34th week because of (i) eclampsia or severe
preeclampsia or (ii)features of placental insufficiency; or
(c) 3/> unexplained consecutive spontaneous abortions before
10th week, with maternal anatomic or hormonal abnormalities
and paternal and maternal chromosomal causes excluded.

8. Laboratory criteria :
1. Lupus anticoagulant present in plasma
2. acL of IgG and/or Igm isotype -medium or
high titer
3. Anti–b-2-GP I IgG and/or Igm isotype
2/> occasions at least 12 weeks apart.

9. • “Definite’’ APLS -persistent high-titer aPL
with one clinical criteria.
• Laboratory criteria- acL IgG or Igm or lupus
anticoagulant in high titers (>40 IgG or Igm or
>99th percentile), confirmed on repeat testing 12
weeks later

10. • Classification like Iry or 2ry APLS is not useful
at all.
• Instead it is with or without the risk factors for
thrombosis.
• Clinical manifestations- No symptoms to
imminently life-threatening, catastrophic APS
(CAPS).

11. Additional risk factors for thrombosis
• Age (M-> 55 , F-> 65 )
• Risk factor for CVD- HT, DM, elevated LDL or low HDL, smoking, F/H
premature CAD, BMI ≥ 30, microalbuminuria, eGFR < 60 ml/min.
• Inherited thrombophilias
• OCP
• Nephrotic syndrome
• Malignancy
• Immobilization
• Surgery

12. Venous Thrombosis
• Typically DVT in L/L.
• Unusual sites – U/L, intracranial veins, IVC,
SVC,hepatic veins (Budd-Chiari syndrome),
portal vein, renal vein & retinal vein. Rarely
superior sagital sinus.
• Thrombosis of the cerebral veins -acute cerebral
infarction.

13. Arterial Thrombosis
• Less common than venous thromboses.
• Most commonly –TIA or stroke (50%) or MI (23%).
• aCL - risk factor for 1st stroke.
• May involve large and small vessels(unusual in thrombophilic
disorders or ATH disease).
• Sites- brachial and subclavian, axillary artery (aortic arch
syndrome), aorta, iliac, femoral, renal, mesenteric, retinal, and
other peripheral arteries.

15. Cardiac Disorders
• CAD- thrombotic or embolic.
• Premature ATH accelerated by aPL.
• Routine aPL tests in CAD not recommended unless young age and
lack of identifiable risk factors suggest a rare etiology.
• Valvular thickening, vegetations, regurgitation, premature CAD,MI,
DCM, CCF, PE, and pul.HT.

16. Neurologic Disorders
• Ischemic stroke.
• Recurrent small strokes -multiple-infarct dementia.
• Typical APLS with stroke- young and lack other classical risk factors
of stroke!
• Chorea, migraine headache, Sneddon’s syndrome, seizures,
transverse myelitis, GBS, IIH, cognitive dysfunction, psychosis, and
optic neuritis are other effects.

17. • Multiple sclerosis-like presentation -cognitive dysfunction and
abnormal MRI.
• Chorea, migraine, seizure, and dysarthria -APLS
• Optic neuritis, bowel and bladder abnormalities, and gait
disturbances -multiple sclerosis.
• In APLS -abnormalities are nonenhancing with gadolinium & high
titer anti-body.

18. Obstetrical Disorders
• Miscarriages and early fetal loss.
• Eclampsia, IUGR, oligohydramninos, HELLP syndrome,
and premature birth, systemic and pulmonary
hypertension.
• Of all hereditary and acquired thrombophilias, APLS is
the most common thrombotic defect leading to
fetal wastage!

19. Dermatologic Disorders
• May be the first sign of APLS.
• Histopathologically -noninflammatory vascular thrombosis.
• Livedo reticularis, necrotizing vasculitis, livedoid vasculitis, cutaneous
ulcerations and necrosis, erythematous macules, purpura, ecchymoses,
painful skin nodules, and subungual splinter hemorrhages.
• Anetoderma, DLE, cutaneous T-cell lymphoma, and disorders similar to
Degos and Sneddon’s syndrome
• Livedo reticularis and APLS frequently -cardiac and cerebral thrombotic
events, epilepsy, and migraine adaches.

20. Levido reticularis.

21. Pulmonary
• Antiphospholipid lung syndrome- thromboembolism,
pulmonary HT, ARDS, postpartum syndrome, and
others.
• Diffuse alveolar haemorrhages.

22. Abdominal Manifestations

23. Renal manifestations
• aPLassociated nephropathy (APLN)
• Thrombosis – RAS and/or malignant hypertension, renal infarction,
renal vein thrombosis, thrombotic microangiopathy, increased
allograft vascular thrombosis, and reduced survival of renal
allografts.
• Non-thrombotic conditions- glomerulonephritis.

24. Endocrine manifestations
• Adrenal insufficiency - most common.
• Circulating aPL- autoimmune thyroid disease,
hypopituitarism (including a case of Sheehan’s
syndrome), DM and rarely ovarian and testicular disease.

25. Retinal Disorders
• Venous and arterial thrombosis of the retinal
vasculature.
• Presentation strongly suggestive - diffuse occlusion of
retinal arteries, veins, or both, and neovascularization at
the time of presentation.
• optic neuropathy and cilioretinal artery occlusion.

26. Hematological Disorders
• Thrombocytopenia (<100,000) -20% to 40%.(usually mild)
• Severe thrombocytopenia -CAPS and DIC or TTP.
• aPL-associated thrombocytopenia –aPL with thrombocytopenia
(<100,000) confirmed 12 weeks apart and exclusion of TTP, DIC,
pseudothrombocytopenia, or HITT.

27. Catastrophic Antiphospholipid
Antibody Syndrome (CAPS)
• A syndrome of multisystem involvement as a manifestation of APLS
(Asherson’s syndrome).
• Less than 1% of APLS patients.
• Multiple small-vessel occlusions leading to MOF and substantial
morbidity and mortality.
• Generally of acute onset and defined by involvement of at least three
different organ systems over a period of days or weeks.

28. • Histopathologically- small- and large-vessel occlusions.
• The striking feature of the syndrome- presence of an
acute microangiopathy, rather than large-vessel
occlusions.

29. CAPS-presentation..
• Clinical features- organ and tissue ischemia
o Renal failure -renal thrombotic microangiopathy,
o Acute respiratory failure -ARDS
o Cerebral injury -microthrombi and microinfarctions
o myocardial failure -microthrombi
• It develops rapidly following an identifiable triggering factor.
• Trigger factors -Infection, trauma, neoplasia, anticoagulation
withdrawal, during pregnancy or peurperium, surgery, and lupus
flares.

30. Preliminary criteria for the
classification of CAPS
1. Evidence of involvement of 3 organ systems, and/or tissues.
 Usually clinical evidence of vessel occlusions, confirmed by imaging.
 Renal involvement -50% rise in S.creatinine, severe HT (>180/100), and/or
proteinuria (>500 mg/24h).
2. Development of manifestations simultaneously or in <1 week.
3. Confirmation by histopathology of small-vessel occlusion in at least
one organ/tissue.-significant evidence of thrombosis, although
vasculitis may coexist.
4. Laboratory confirmation of the presence of aPL (lupus anticoagulant
and/or aCL and/or anti b2 GP I)
• Definite CAPS
All four criteria

31. .Probable CAPS
Criteria 2, 3 & 4, plus 2 organs involved.
• All four criteria, except for the absence of laboratory confirmation of
the presence of aPL at least 6 weeks after a first positive result
• Criteria 1,2 & 4
• Criteria 1,3 & 4, plus the development of a third event in >1 week but
<1 month, despite anticoagulation treatment.

32. • Cerebral involvement, mainly stroke, followed by cardiac
involvement and infections -main causes of death.
• The presence of SLE - related with higher mortality!

33. Asymptomatic Antiphospholipid
Antibodies
• Line between asymptomatic aPL and APLS- development of large or
small-vessel thrombosis or pregnancy loss.
• Risk factors for transition to APLS –P/H thrombosis, lupus
anticoagulant & elevated aCL IgG.
• Each risk factors increase the risk of thrombosis by fivefold.
• Persistence aPL over time progressively increases thrombosis risk.
• keep the asymptomatic under clinical surveillance for thrombosis.

34. Probable APLS/pre APLS
• Positive aPL with clinical features suggesting APLS but
lack the clinical criteria.
• C.F: livedo reticularis, chorea, thrombocytopenia, fetal
loss, and cardiac valvular lesions.
• Livedo reticularis -1st manifestation of APLS (41% of
patients).

35. Seronegative APLS (SNAP)
• Clinical manifestations of APLS, without any recognized
aPL.
• Idiopathic arterial or venous thrombosis and initial
testing for aPL is negative. Repeat testing months later
may be positive

36. Microangiopathic APLS
• APLS may present with characteristic of microvascular
occlusive disease. Eg: TTP, HELLP,Thrombotic MAHA
& CAPS.

37. Drug-Induced APLS
• Eg: chlorpromazine, phenytoin, hydralazine,
procainamide, fansidar, quinidine, interferon, and
cocaine.
• A common misconception -often immunoglobulin (Ig)
M, do not suffer thrombosis.

38. Infection-Associated APLS
• Autoantibodies are more often IgM than IgG.
• The C.F of typical of APS are less commonly observed.
• Infections associated with aPL and β-2-GP I – associated
with thrombosis (leprosy, parvovirus B19, HIV, HCV,
CMV)
• Infection -triggering factor in 40% of cases of CAPS.

39. Malignancy-Associated APLS
• A variety of solid and hematologic malignancies
associated with the presence of aPL.

40. Antiphospholipid Syndrome Antibodies
• Target PL directly- cardiolipin, phosphatidylserine,
phosphatidylinositol,phosphatidylethanolamine,
phosphatidylglycerol, and phosphatidylcholine.
APAs -IgG, IgA, and IgM.
• APS antibodies against protein antigens –anionic PL, forming a
protein-phospholipid complex. Eg- beta-2-glycoprotein I(β2-GPI)
and prothrombin.
• antibodies against annexin V and protein C associated with APLS
&SLE.

41. Lupus anti coagulant(LA)
• Misnomer, associated with thrombosis and not bleeding
• LA inhibits formation of prothrombinase complex.
• It blocks binding of prothrombin and factor Xa to phospholipids,
(conversion of prothrombin to thrombin).
• LA can be- IgG, IgA, or IgM.
• LA is found in 10% of SLE.
• LA commonly ass. with venous thrombosis & occasionally arterial
disease

42. • When clinical APLS & assays for ACAs or LACs are
negative- anti-β2-GpI and antibodies to
phosphatidylserine phosphatidylethanolamine,
phosphatidylglycerol, phosphatidylinositol, annexin-V,
and phosphatidylcholine need to be arranged.

43. Management of APLS

45. • Prophylactic dose- Enoxaparin 30–40 mg
subcutaneously daily.
• Therapeutic dose- Enoxaparin 1mg/kg S/C bd or 1.5
mg/kg/d.
• APLS with cerebral ischaemia -target INR of 3.0 to
prevent recurrences. (Low-dose aspirin alone does not
seem helpful here)
• Once proven thrombosis -long-term (possibly life-
long) warfarin therapy is advisable.
• Reduce the modifiable vascular risk factors.

46. • No data indicate the efficacy of warfarin
microangiopathic nephropathy, valvular heart disease,
livedo reticularis, or leg ulcers.
• No data support its use in asymptomatic bearers of aPL.

47. • Ximelagatran is the first oral thrombin inhibitor. The active
metabolite- melagatran -wider therapeutic window, rapid onset of
action, and shorter half-life than warfarin.
• Ximelagatran – no drug interaction
• Ximelagatran is superior to warfarin -prevention of venous
thromboembolism after total KJ replacement.
• Good results have been reported with autologous hematopoietic
stem cell transplantation (HSCT) in APLS

49. Summary….
• Main 3antibodies in APLS- LA,ACL, Anti-b2GPI.
• If all negative with clinical suspician of APLS need further antibody
testing.
• Risk factor assessment for thrombosis is important than Iry or IIry.
• Lab criteria -extension of the interval between first and second
positive test from 6 to 12 weeks.
• Recognition of other features that serve as diagnostic clues.
• Seronegative APLS (SNAP).
• CAPS is rare but lethal.

50. References
• Update article in Antiphospholipid antibody syndrome; Renu
saigal.Amit Kansal,Manoop Mittal,Yadvinder Singh,Hari
Ram;JAPI.MARCH 2010.VOL 58

51. Thank you!